Research worldwide is currently underway to develop treatments and cures for Herpes Simplex Virus (HSV) Types 1and 2. Both HSV Type 1 and 2 show a predilection for infection of the ectodermal tissues wherein such infections by the virus cause lesions in the skin, oral cavity, vagina, conjunctiva, and the nervous system. Generally, infection by HSV Type 1 (HSV1) is associated with oral, facial and ocular lesions. Infection by HSV Type 2 (HSV2) generally results in genital and anal lesions. HSV infections left untreated often lead to blindness, neonatal deaths, and encephalitis. HSV Type 2 infections are at an epidemic portion in the US from venereal transmission. Greater than some twenty million persons are presently afflicted with the disease in this country with new cases and recurrences exceeding half a million annually. The annual cost of HSV infections results in a substantial economic loss to diagnose and treat. Epidemiological control of HSV is poor because the majority of the population, up to 90%, has been exposed to the virus.
Man serves as the natural host for HSV Type 1 and 2 infections whereby the virus is transmitted during close personal contact. Initial or primary infections by HSV Types 1 and 2 are contracted through breaks in the mucus membrane. In the healthy carrier the virus can be isolated in the tears, saliva, vaginal and other secretions, even during the absence of overt disease. From the mucus membrane they are able to replicate and spread to the regional lymph nodes. Occasionally these viruses can infect cells of the haemopoietic system and cause viremia.
Part of the difficulty to treat HSV infections results from the ability of these viruses to persist in a latent, or quiescent form. When the primary infection subsides or recedes, the virus generally resides in a latent form in the sensory nerve ganglia which innervate the site of primary infection. In ocular or oral infections with HSV Type 1, the virus generally resides in the trigeminal ganglia. In HSV Type 2 the viruses generally resides in the sacral ganglia serving the genitalia and lower abdoman. The determinative period of latency of the HSV virus is unknown, other than this period can be upset by heat, cold, sunlight, hormonal and emotional disturbances, or by immunosuppressive agents, resulting generally in a recurrent infection.
Treatment of HSV infections have largely been ineffective. A number of strategies to stop the virus have been developed. These agents generally inhibit any one of a number of specific viral functions such as (1) adsorption, (2) uncoating, (3) transcription, (4) protein synthesis, (5) nucleic acid replication, (6) maturation, and (7) release.
Most of the antiviral agents thus far used to treat HSV infections have been compounds that interfere with vital DNA. These compounds include Idoxuridine, Cytosine Arabinoside, Adenine Arabinoside, Trifluorothymidine and Acyclovir. Such agents also interfere with similar host functions which results in general problems with cell toxicity and systemic use in humans. Presently, Acyclovir is the preferred medication to treat infections with HSV1 and HSV2 due to its potent antiviral effect and negligable toxicity. Poor solubility at high dosage and the emergence of drug-resistant viruses, however, limit the use of this drug.
A number of RNA and DNA containing viruses have envelopes into which virus-coded glycopeptides are incorporated. HSV is one of the enveloped viruses. Infection of a host cell by enveloped viruses initially relies on the interaction of various receptors on the host cell surface with the envelope glycoproteins of the vital membrane. Subsequently the virus and cell membranes fuse and the virion contents are released into the host cell cytoplasm. The glycoprotein containing envelope of the virus plays an important role in both the initial interaction of the virion and the host cell and in the later fusion of the viral and host cell membranes. The viral envelope seems to be derived from the cellular membrane, but the specificity is due to the viral encoded glycopeptides. Therefore, an inhibitor capable of interfering with the formation of the virus-specific membranes may prevent formation of infectious progeny virus.
Interference with the formation of the viral envelope glycoprotein could prevent the initial virus-host cell interaction or subsequent fusion or could inhibit vital replication by preventing the required synthesis of glycoproteins to produce infectious virions. It has been recently reported that the nonspecific inhibitors of glycosylation, 2-deoxy-D-glucose and .beta.-hydroxy-norvaline inhibit expression of HIV glycoproteins and block the formation of syncytia. H. A. Blough, et al., Biochemical and Biophysical Research Communications, 141(1), 33-38 (1986). Furthermore, 2-deoxy-D-glucose is also active against HSV and has shown efficacy in the treatment of Herpes infections in man. In another report, the glycosylation inhibitor 2-deoxy-2-fluoro-D-mannose was found to exhibit antiviral activity against influenza infected cells by preventing the glycosylation of viral membrane protein (W. McDowell, et al., Biochemistry, 24(27), 8145-52 (1985)). This report also studied the antiviral activity of 2-deoxyglucose and 2-deoxy-2-fluoroglucose and found that each inhibit viral protein glycosylation by a different mechanism. Many other known glycosylation inhibitors are found to have no antiviral activity. Thus the antiviral activity of inhibitors of glycosylation per se are quite unpredictable.
Inhibitors of the processing enzymes involved in the shaping of the oligosaccharide portion of the viral glycoprotein may provide more selectivity in their mechanism of action. The applicants' have found that certain compounds derived from Castanospermine are effective against the viral processing enzyme and therefore are potentially useful in the treatment of HSV infections.
Castanospermine is an alkaloid, originally isolated from the seeds of Castanospermum australe having the following formula: ##STR3## Systematically, this compound can be named in several ways as follows: [1S-(1.alpha., 6.beta., 7.alpha., 8.beta., 8.alpha..beta.)]-octahydro-1,6,7,8-indoli-zinetetrol or [1S,(1S,6S,7R,8R,8aR)-1,6,7,8-tetrahydroxy-indolizidine or 1,2,4,8-tetradeoxy-1,4,8-nitrilo-L-glycero-D-galacto-octitol. The term "castanospermine" or the first systematic name will be used in the discussion below.
The isolation of this compound and the determination of its structure has been described by L. D. Hohenshutz,. et al., Phytochemistry, 20, 811 (1981). As part of his study of castanospermine, Hohenshutz obtained castanospermine tetraacetate by the reaction of castanospermine with a very large excess of acetic anhydride but there is no suggestion of any other esters of castanospermine in the article.
The applicants have now discovered that certain esters of castanospermine that are potent inhibitors of the glycoprotein processing enzymes that are considered to be a requiste to correctly synthesize viral glycoproteins. The castanospermine esters are therefore considered to be useful in the treatment of various HSV infections.